Male sexual dysfunction (MSD) is a mixed group of complaints that are typically related to a person's inability to respond sexually or to achieve sexual stimulation. Male sexual dysfunction is a common problem mainly associated with erectile dysfunction (ED) and/or premature ejaculation (PE). ED has many causes such as adverse results of using prostate cancer treatment, after exposure to radiotherapy, atherosclerosis problems, as well as those with cardiovascular diseases or diabetes mellitus (Pisansky et al., 2014; Satriyasa, 2017). It was reported that by 2025 ED is expected to affect about 322 million men around the world. The prevalence of PE ranges from 19% to 30% in the general population and is considered the most common sexual dysfunction in men (Gao et al., 2013; Serefoglu et al., 2011). Patient numbers with male sexual dysfunction are expected to double in the next twenty-five years (Ramezani et al., 2015). PE is present in up to 30% of men with ED (Rastrelli et al., 2019). Thus, ED and PE may be considered as an interconnected case of sexual dysfunction.
A potent and selective phosphodiesterase-5 inhibitor (PDE5-I), tadalafil (TDL) is one of the most efficient medicines for the treatment of ED (Andersson, 2018). On the other hand, a selective serotonin reuptake inhibitor (SSRI), dapoxetine (DPX) is has been approved for the treatment of PE (Li et al., 2018; Althof et al., 2010). It is the first oral pharmacological agent used, and the only SSRI approved in more than 60 countries to treat men with PE (Park et al., 2017).
On comparing the on-demand dosing of DPX alone and combined with PDE5-I in subjects with PE and without ED, it was found that a low dose of DPX combined with PDE5-I showed better outcomes compared with that of DPX only. This finding supports the recommendation that the PDE5-Is have a potential role in the treatment of PE without ED (Lee et al., 2013). In addition, the combined use of SSRIs and PDE5-Is provided additive favorable effects in men with PE compared with SSRIs or PDE5-I monotherapy (Bai et al., 2015). Moreover, DPX provided a remarkable treatment benefit in men with PE and comorbid ED on a stable regimen of PDE5-I (Mcmahon et al., 2013). Finally, it was reported that the combination of DPX with TDL is well tolerated and the concomitant administration of TDL and DPX did not affect the pharmacokinetics of both APIs (Dresser et al., 2006).
However, TDL undergoes low bioavailability due to its inherent poor aqueous solubility (Badr-Eldin et al., 2017; Badr-Eldin et al., 2008). Also, DPX suffers from low and variable oral bioavailability that ranges from 15-76% (El-Say et al., 2019). This low and variable drug concentration in the blood may lead to decreased efficacy and/or exaggerated side effects.
To overcome this hurdle that encounters the formulators of the oral solid dosage form, many researchers have developed various approaches to improve drug water-solubility such as the adjustment of the pH, the addition of cosolvent, particle size reduction, solid dispersion (Pandya, 2010), salt formation or formulation of the drug in lipid-based nanovesicles such as liposomes (Sanjay et al., 2013), nanosuspension development (Patel et al., 2011)(Keck and Müller, 2006), prodrug synthesis (Erion et al., 2005), formation of micro- and nano-particles (El-Say and El-Sawy, 2017), or incorporation of drugs into porous structure and nanoemulsion formulations (El-Say et al., 2017)(Ahmed et al., 2018).
However, new formulations that improve the solubility and enhance the bioavailability of tadalafil and dapoxetine are needed.